Impact of Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene in the vulnerability to cocaine addiction induced by chronic stress

BOEZIO M. JULIETA; RIGONI DAIANA; CANCELA LILIANA M; ANASTASIA AGUSTÍN; BOLLATI FLAVIA

Congreso; XXXIV Congreso de la Sociedad Argentina de Investigación en Neurociencias; 2019

Sociedad Argentina de Investigación en Neurociencias

The main goal of this project is to evaluate the influence of a single-nucleotide polymorphism (SNP) on the brain-derived neurotrophic factor (BDNF) gene that leads to a substitution valine (Val) to methionine (Met) at codon 66 (Val66Met) in our model of cross sensitization between stress and cocaine. Recently, this polymorphism has been associated with stress disorders, depression and substance abuse vulnerability in the human population. The current study will use an inbred genetic knock-in mouse strain that expresses the variant BDNF allele, in which the Val66Met polymorphism is expressed endogenously, to recapitulate the specific phenotypic properties of the human polymorphism on the vulnerability to develop cocaine addiction induced by stress.We will evaluate the molecular and structural changes generated in the two subdivisions of nucleus accumbens (NA), core vs shell, as well as the relevance of these changes in behavioral effects generated in response to stress and cocaine. We will also investigate the signaling pathways involving the RhoGTPase Rac1, since it has been described that the Val66Met polymorphism of the BDNF pro-domain causes an alteration in the regulation of Rac1 activity. Rac1 protein is involved in the regulation of the actin cytoskeleton dynamics in dendritic spines and in neuronal plasticity induced by cocaine. Our hypothesis proposes that the activity of the BDNF pro-domain containing the Met substitution is a mechanism that could contribute to the vulnerability to cocaine addiction induced by stress, through the regulation of Rac1 activity.